The goal in the treatment of cancerous tumors and micrometastases has long been to kill the cancerous cells without killing healthy cells. Today, in the development of new short-range, site-specific therapies, there is increasing interest in using radioisotopes which decay with the emission of alpha particles. Indeed, recent clinical trials have shown the effectiveness of the alpha-emitter bismuth-213 in killing cancer cells in patients with acute myeloid leukemia. In addition, lung tumors in mice have been effectively treated for the first time by using an antibody radiolabeled with bismuth-213, targeting the lung vascular endothelial cells.
Alpha-particles are of interest in site-specific therapy because of their short range. Bismuth-213 emits an 8 MeV alpha particle which penetrates only 6 to 10 cell layers nearby, killing the cells in its short path (˜80 μm), including cancer cells. In addition to bismuth-213, there are only eight other known alpha-emitters with potential for this type of application, namely, astatine-211, bismuth-212, lead-212, radium-223, radium-224, radium-225, actinium-225, and fermium-255.
There are a number of factors that need to be considered in using any radioisotope in humans, especially those radioisotopes emitting alpha particles. These factors include availability, cost, nuclear characteristics, chemistry, and in vitro and in vivo stability of the biomolecules labeled with alpha-emitters. The first two alpha-emitters to be used in human trials are bismuth-213 and astatine-211; the other seven radioisotopes mentioned above are under more preliminary investigations. Bismuth-213 is currently being used in human trials at Memorial Sloan-Kettering Cancer Center (New York) and is generated in-house from the decay of actinium-225. This radioisotope is produced from the decay of radium-225, which is the daughter of thorium-229, which, in turn is the alpha decay daughter of uranium-233.
Currently, uranium-233 is the only viable source for high purity thorium-229. However, the anticipated growth in demand for actinium-225 may soon exceed the levels of thorium-229 present in the aged uranium-233 stockpile (in fact, there have been occasions that supply has not been able to keep up with the current demand). It is estimated that only ˜45 g or ˜9 curies of thorium-229 (229Th specific activity is 0.2 mCi/mg) can be extracted from entire uranium-233 stockpile at the Oak Ridge National Laboratory (hereinafter “ORNL”). The uranium-233 stockpile at ORNL is about 50% of the high quality uranium-233 available in the world which provides reasonably low quantities of both Th-228 and Th-232. This stockpile is only about eighty times the current thorium stock. Large quantities of Th-228 or Th-232 can make the use of a uranium-233 stockpile impractical. Considering the rather low annual production rate of thorium-229 from uranium-233 (0.92 mCi/kg) and the increasing difficulties associated with uranium-233 safeguards, large-scale routine processing of uranium-233 is, at a minimum, problematic.
A number of approaches have been identified as alternative routes for the production of 229Th(t1/2=7340 y), or for direct production of 225Ra(t1/2=15 d), and 225Ac (t1/2=10 d). These approaches include a) production of 229Th in a nuclear reactor by thermal neutron transmutation of 226Ra targets, b) direct production of 225Ac from proton and deuteron irradiation of 226Ra targets via the [p,2n] and [d,3n] reactions, respectively, at accelerators, and c) indirect production of 225Ac from the decay of 225Ra which in turn is produced by high energy γ-ray irradiation of a 226Ra target, [γ,n] reactions. The alternate route (a) noted above produces a low yield of 229Th.